PROJECT SUMMARY Currently available HIV formulations necessitate lifelong, daily dosing and after prolonged periods of time, patients can encounter pill fatigue and frequently miss doses of their medication. This can have detrimental consequences on the success of therapy, increasing likelihood of the virus developing resistance to the drugs used. Recently, innovations by leading pharmaceutical companies have demonstrated the potential for long- acting formulations that enable the drugs to be administered just once a month (or even less frequently) but sustain delivery of drug over that period. Although this has the potential to greatly impact the dosing frequency, a major limitation of this approach is the need for effective treatments to use simultaneous combinations of different drugs, and only two drugs have been developed with long-acting formulations. This means that patients must still take daily oral tablets from a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). The two industrial long-acting therapeutic candidates (rilpivirine LA and cabotegravir LA) were manufactured using a milling process that generates solid drug nanoparticles from poorly water-soluble drugs. NRTIs have inherent water-solubility and are, therefore, currently incompatible with the technologies being utilized by pharmaceutical companies to produce long-acting formulations. Using our recent advances in polymer chemistry, prodrug chemistry, pharmacology and predictive modelling we propose to generate and optimize long-acting backbone regimens consisting of NRTIs to match current standard of care and compliment the recent industrial developments. A series of four NRTIs will be studied and we will assess two administration options that will establish the utility for long-acting NRTI delivery and define a new platform technology for many water-soluble drugs. Iteration between the different disciplines involved within the collaborative program will ensure clinically-relevant options are developed which are shelf-stable, and release NRTIs over at least a one-month period. Translation will be de-risked through early safety evaluation. The robustness of each candidate generated, its scalability, sterility and cost effectiveness will also be established. To deliver this ambitious program, each candidate will undergo a sequential and detailed preclinical evaluation of their pharmacology and safety, to enable optimization of favorable properties. Lead candidates will be selected for analysis in vivo by integrating laboratory data through mathematical modeling. Our strategy will develop candidates for long-acting NRTIs and generate proof-of-concept to support future work and attract third party interest. Impact will derive from a new platform for long-acting release and benefits to patients through simplification of therapies and dosing frequency.